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Monday, December 8, 2014

Yesterday, ISIS Pharmaceuticals disclosed in-depth data from
their phase II anti-clotting study in about 300 patients undergoing total knee
arthroplasty (TKA). This took place at the American Society of Hematology (ASH) meeting
alongside a publication in the New England Journal of Medicine (Bueller et al. 2014). The data for the first time
provide striking evidence that it is possible to dissociate anti-clotting activity
from a commensurate increase in the risk of bleeding.

Accordingly, while the 200mg per week dose (moderate 59% FXI knockdown) achieved a rate of venous thromboembolism (VTE) similar to the enoxaparin standard-of-care comparator in the trial (27% and
30%, respectively), at the 300mg per week dose (much more robust 78% FXI knockdown) the VTE rate dropped by 7-fold to just 4%.

At the same time, bleeding risk remained the same, if not
better for ISIS-FXIRx vs enoxaparin: 3% bleeding events for both FXI cohorts vs 8% for enoxaparin, albeit this was not a statistically significant
difference.

In terms of safety and tolerability, ISIS-FXIRx resulted in
mild local skin reactions in 6.6% of the injections, but leading to no
discontinuations. Moreoever, no flu-like symptoms were recorded. This is a stark departure from ISIS’ legacy
drug mipomersen which suffered from frequent flu-like symptoms and injection site
reactions resulting in relatively frequent drug discontinuations.

Challenging the paradigm

Until now, it has been widely thought that
whenever you develop a new, more powerful anticoagulant, you will pay the price
of more bleeding. This has meant not
only much development money wasted, but also created important
market needs such as in patients which require anticoagulants with lower bleeding risks.

It is these markets, including patients with end-stage renal disease and atrial fibrillation, that ISIS Pharmaceuticals will address
first as it seeks a partner more familiar with the complexities of the anti-clotting
market.

What seems to underlie the surprising results is that with
Factor XI you are targeting the intrinsic branch of the clotting cascade which prevents the formation of large clots that may travel around the body often
with fatal consequences, but without impeding the ability to form small clots
when healing tissue damage following trauma caused by external factors.

By contrast, conventional anticoagulants such as enoxaparin
(a heparin derivative), Factor Xa and thrombin inhibitors interfere with both
processes.

Challenging the establishment

The strategy of addressing niches of high
unmet need in the anticlotting market first is not only explained by potentially faster orphan-type
development timelines, but also by the fact that by presenting such disruptive
data in a multi-billion market, ISIS can be expected to encounter stiff
resistance from the anti-clotting establishment.
This refers not only to competing pharmaceutical companies, but also
their associated key opinion leaders from academia that enjoy a
gate-keeper function partly due to the regulators commonly seeking their
advice.

So given that the efficacy results are undoubtedly impressive,
expect over the coming days, months, if not years to hear the message that the ISIS-FXIRx data ‘might’ be a proof-of-principle for dissociating clotting from bleeding for
anticoagulant therapy, but that this 300-patient study needs to be replicated
in a larger population and that there are ‘concerns’ around the tolerability and
convenience of ISIS-FXIRx, all the while the same groups are busy catching up
developing antibody- and small molecule-based versions of anti-Factor XI drugs.

Couple of errors in your blog. One patient was dosed at 0.045 mg/kg and not at 0.045 mcgm/kg as you mentioned. Second, it was ED80 at 0.5 mg/kg with weekly dosing in NHP and not ED90 as per Alnylam slides.

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